Involvement of non-esterified fatty acid oxidation in glucocorticoid-induced peripheral insulin resistance in vivo in rats

Diabetic db/db mice exhibit profound insulin resistance in vivo, but the specific degree of cardiac insensitivity to insulin has not been assessed. Therefore, the effect of insulin on cardiomyocytes from db/db hearts was assessed by measuring two metabolic responses (deoxyglucose uptake and fatty acid oxidation) and the phosphorylation of two enzymes in the insulin-signaling cascade [Akt and AMP-activated protein kinase (AMPK)]. Maximal insulin-stimulated deoxyglucose transport was reduced to 58 and 40% of control in cardiomyocytes from db/db mice at two ages (6 and 12 wk). Insulin-stimulated deoxyglucose uptake was also reduced in myocytes from transgenic db/db mice overexpressing the insulin-sensitive glucose transporter ( db/db-hGLUT4). Treatment of db/db mice for 1 wk with an insulin-sensitizing peroxisome proliferator-activated receptor-γ agonist (COOH) completely normalized insulin-stimulated deoxyglucose uptake. Insulin had no direct effect on palmitate oxidation by either control or db/db cardiomyocytes, but the combination of insulin and glucose reduced palmitate oxidation, likely an indirect effect secondary to increased glucose uptake. Insulin had no effect on AMPK phosphorylation from either control or db/db cardiomyocytes. Insulin increased the phosphorylation of Akt in all cardiomyocyte preparations (control, db/db, COOH-treated db/db) to the same extent. Thus insulin has selective metabolic actions in mouse cardiomyocytes; deoxyglucose uptake and Akt phosphorylation are increased, but fatty acid oxidation and AMPK phosphorylation are unchanged. Insulin resistance in db/db cardiomyocytes is manifested by reduced insulin-stimulated deoxyglucose uptake.

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Reduced Cardiac Efficiency and Altered Substrate Metabolism Precedes the Onset of Hyperglycemia and Contractile Dysfunction in Two Mouse Models of Insulin Resistance and Obesity

Endocrinology ◽

10.1210/en.2005-0938 ◽

2005 ◽

Vol 146 (12) ◽

pp. 5341-5349 ◽

Cited By ~ 343

Author(s):

Jonathan Buchanan ◽

Pradip K. Mazumder ◽

Ping Hu ◽

Gopa Chakrabarti ◽

Matthew W. Roberts ◽

...

Keyword(s):

Insulin Resistance ◽

Fatty Acid ◽

Fatty Acid Oxidation ◽

Mouse Models ◽

Acid Oxidation ◽

Contractile Dysfunction ◽

Oxidation Rates ◽

Myocardial Substrate ◽

Old Mice

Hyperglycemia is associated with altered myocardial substrate use, a condition that has been hypothesized to contribute to impaired cardiac performance. The goals of this study were to determine whether changes in cardiac metabolism, gene expression, and function precede or follow the onset of hyperglycemia in two mouse models of obesity, insulin resistance, and diabetes (ob/ob and db/db mice). Ob/ob and db/db mice were studied at 4, 8, and 15 wk of age. Four-week-old mice of both strains were normoglycemic but hyperinsulinemic. Hyperglycemia develops in db/db mice between 4 and 8 wk of age and in ob/ob mice between 8 and 15 wk. In isolated working hearts, rates of glucose oxidation were reduced by 28–37% at 4 wk and declined no further at 15 wk in both strains. Fatty acid oxidation rates and myocardial oxygen consumption were increased in 4-wk-old mice of both strains. Fatty acid oxidation rates progressively increased in db/db mice in parallel with the earlier onset and greater duration of hyperglycemia. In vivo, cardiac catheterization revealed significantly increased left ventricular contractility and relaxation (positive and negative dP/dt) in both strains at 4 wk of age. dP/dt declined over time in db/db mice but remained elevated in ob/ob mice at 15 wk of age. Increased β-myosin heavy chain isoform expression was present in 4-wk-old mice and persisted in 15-wk-old mice. Increased expression of peroxisomal proliferator-activated receptor-α regulated genes was observed only at 15 wk in both strains. These data indicate that altered myocardial substrate use and reduced myocardial efficiency are early abnormalities in the hearts of obese mice and precede the onset of hyperglycemia. Obesity per se does not cause contractile dysfunction in vivo, but loss of the hypercontractile phenotype of obesity and up-regulation of peroxisomal proliferator-activated receptor-α regulated genes occur later and are most pronounced in the presence of longstanding hyperglycemia.

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Muscle acylcarnitines during short-term fasting in lean healthy men

Clinical Science ◽

10.1042/cs20080433 ◽

2009 ◽

Vol 116 (7) ◽

pp. 585-592 ◽

Cited By ~ 48

Author(s):

Maarten R. Soeters ◽

Hans P. Sauerwein ◽

Marinus Duran ◽

Ronald J. Wanders ◽

Mariëtte T. Ackermans ◽

...

Keyword(s):

Insulin Resistance ◽

Fatty Acid ◽

Fatty Acid Oxidation ◽

Glucose Oxidation ◽

Acid Oxidation ◽

Healthy Humans ◽

Peripheral Insulin Resistance ◽

Acid Metabolites ◽

Fatty Acid Metabolites ◽

Long Chain

The transition from the fed to the fasted resting state is characterized by, among other things, changes in lipid metabolism and peripheral insulin resistance. Acylcarnitines have been suggested to play a role in insulin resistance, as well as other long-chain fatty acid metabolites. Plasma levels of long-chain acylcarnitines increase during fasting, but this is unknown for muscle long-chain acylcarnitines. In the present study we investigated whether muscle long-chain acylcarnitines increase during fasting and we investigated their relationship with glucose/fat oxidation and insulin sensitivity in lean healthy humans. After 14 h and 62 h of fasting, glucose fluxes, substrate oxidation, and plasma and muscle acylcarnitines were measured before and during a hyperinsulinaemic–euglycaemic clamp. Hyperinsulinaemia decreased long-chain muscle acylcarnitines after 14 h of fasting, but not after 62 h of fasting. In both the basal state and during the clamp, glucose oxidation was lower and fatty acid oxidation was higher after 62 h compared with 14 h of fasting. Absolute changes in glucose and fatty acid oxidation in the basal compared with hyperinsulinaemic state were not different. Muscle long-chain acylcarnitines did not correlate with glucose oxidation, fatty acid oxidation or insulin-mediated peripheral glucose uptake. After 62 h of fasting, the suppression of muscle long-chain acylcarnitines by insulin was attenuated compared with 14 h of fasting. Muscle long-chain acylcarnitines do not unconditionally reflect fatty acid oxidation. The higher fatty acid oxidation during hyperinsulinaemia after 62 h compared with 14 h of fasting, although the absolute decrease in fatty acid oxidation was not different, suggests a different set point.

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MicroRNA-27b-3p regulates function and metabolism in insulin resistance cells by inhibiting receptor tyrosine kinase-like orphan receptor 1

European Journal of Inflammation ◽

10.1177/2058739218762058 ◽

2018 ◽

Vol 16 ◽

pp. 205873921876205

Author(s):

Yong Liu ◽

Guohui Wang ◽

Xiangwu Yang ◽

Pengzhou Li ◽

Hao Ling ◽

...

Keyword(s):

Insulin Resistance ◽

Fatty Acid ◽

Tyrosine Kinase ◽

Glucose Uptake ◽

Fatty Acid Oxidation ◽

Receptor Tyrosine Kinase ◽

Cell Model ◽

Orphan Receptor ◽

Acid Oxidation ◽

Metabolism Disorder

Type 2 diabetes mellitus (T2DM) is associated with insulin resistance-induced lipid and glucose metabolism disorder. The study was aimed to explore the potential functional role of microRNA (miR)-27b-3p in T2DM, as well as underlying mechanisms. An insulin resistance cell model was induced in HepG2 cells and then expression of miR-27b-3p and receptor tyrosine kinase-like orphan receptor 1 (ROR1) was analyzed. The expression of miR-27b-3p was overexpressed or silenced, and the relationship between ROR1 and miR-27b-3p was investigated. Thereafter, the effects of miR-27b-3p on percentage of glucose uptake, fatty acid oxidation and cell cycle were analyzed. The expressions of miR-27b-3p were significantly increased, while the ROR1 levels were statistically decreased in the cells of the model group. Overexpression of miR-27b-3p dramatically decreased the levels of ROR1 and the percentage of glucose uptake, but had no effects on fatty acid oxidation. ROR1 was a target of miR-27b-3p. Moreover, overexpression of miR-27b-3p could remarkably highlight the percentages of cells at G0/G1 phase, but decreased the percentages of cells at S phase. In conclusion, our results suggest that miR-27b-3p regulates the function and metabolism of insulin resistance cells by inhibiting ROR1. miR-27b-3p might be a potential drug target in treating T2DM.

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Critical Role for Hepatocyte-Specific eNOS in NAFLD and NASH

10.2337/figshare.15108567.v1 ◽

2021 ◽

Author(s):

Rory P. Cunningham ◽

Mary P. Moore ◽

Ryan J. Daskek ◽

Grace M. Meers ◽

Takamune Takahashi ◽

...

Keyword(s):

Fatty Acid ◽

Fatty Acid Oxidation ◽

Critical Role ◽

Acid Oxidation ◽

Mitochondrial Fatty Acid Oxidation ◽

Nonalcoholic Fatty Liver ◽

Mitochondrial Fatty Acid ◽

Endothelial Nitric Oxide

Regulation of endothelial nitric oxide synthase (eNOS) in hepatocytes may be an important target in nonalcoholic fatty liver disease (NAFLD) development and progression to steatohepatitis (NASH). In this study, we show genetic deletion and viral knockdown of hepatocyte-specific eNOS exacerbated hepatic steatosis and inflammation, decreased hepatic mitochondrial fatty acid oxidation and respiration, increased mitochondrial H<sub>2</sub>O<sub>2</sub> emission, and impaired the hepatic mitophagic (BNIP3 and LC3II) response. Conversely, overexpressing eNOS in hepatocytes in vitro and in vivo increased hepatocyte mitochondrial respiration and attenuated western diet induced NASH. Moreover, patients with elevated NAFLD activity score (histology score of worsening steatosis, hepatocyte ballooning, and inflammation) exhibited reduced hepatic eNOS expression which correlated with reduced hepatic mitochondrial fatty acid oxidation and lower hepatic protein expression of mitophagy protein BNIP3. The current study reveals an important molecular role for hepatocyte-specific eNOS as a key regulator of NAFLD/NASH susceptibility and mitochondrial quality control with direct clinical correlation to patients with NASH.

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Pomegranate vinegar feeding enhances fatty acid oxidation: In vitro and in vivo

The FASEB Journal ◽

10.1096/fasebj.26.1_supplement.824.2 ◽

2012 ◽

Vol 26 (S1) ◽

Author(s):

YEOJIN PARK ◽

Elly Ok ◽

Hyo Jung Lee ◽

Ji Yeon Kim ◽

Mi Kyung Kim ◽

...

Keyword(s):

Fatty Acid ◽

Fatty Acid Oxidation ◽

Acid Oxidation

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In Vivo Determination of Mitochondrial Function Using Luciferase‐Expressing Caenorhabditis elegans : Contribution of Oxidative Phosphorylation, Glycolysis, and Fatty Acid Oxidation to Toxicant‐Induced Dysfunction

Current Protocols in Toxicology ◽

10.1002/cptx.10 ◽

2016 ◽

Vol 69 (1) ◽

Cited By ~ 8

Author(s):

Anthony L. Luz ◽

Cristina Lagido ◽

Matthew D. Hirschey ◽

Joel N. Meyer

Keyword(s):

Fatty Acid ◽

Caenorhabditis Elegans ◽

Oxidative Phosphorylation ◽

Fatty Acid Oxidation ◽

Mitochondrial Function ◽

Acid Oxidation

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Retinoic Acid Increases Fatty Acid Oxidation and Irisin Expression in Skeletal Muscle Cells and Impacts Irisin In Vivo

Cellular Physiology and Biochemistry ◽

10.1159/000488422 ◽

2018 ◽

Vol 46 (1) ◽

pp. 187-202 ◽

Cited By ~ 15

Author(s):

Jaume Amengual ◽

Francisco J. García-Carrizo ◽

Andrea Arreguín ◽

Hana Mušinović ◽

Nuria Granados ◽

...

Keyword(s):

Skeletal Muscle ◽

Retinoic Acid ◽

Fatty Acid ◽

Glucose Uptake ◽

Fatty Acid Oxidation ◽

Kinase Inhibitor ◽

Acid Oxidation ◽

Peroxisome Proliferator ◽

Protective Effects

Background/Aims: All-trans retinoic acid (ATRA) has protective effects against obesity and metabolic syndrome. We here aimed to gain further insight into the interaction of ATRA with skeletal muscle metabolism and secretory activity as important players in metabolic health. Methods: Cultured murine C2C12 myocytes were used to study direct effects of ATRA on cellular fatty acid oxidation (FAO) rate (using radioactively-labelled palmitate), glucose uptake (using radioactively-labelled 2-deoxy-D-glucose), triacylglycerol levels (by an enzymatic method), and the expression of genes related to FAO and glucose utilization (by RT-real time PCR). We also studied selected myokine production (using ELISA and immunohistochemistry) in ATRA-treated myocytes and intact mice. Results: Exposure of C2C12 myocytes to ATRA led to increased fatty acid consumption and decreased cellular triacylglycerol levels without affecting glucose uptake, and induced the expression of the myokine irisin at the mRNA and secreted protein level in a dose-response manner. ATRA stimulatory effects on FAO-related genes and the Fndc5 gene (encoding irisin) were reproduced by agonists of peroxisome proliferator-activated receptor β/δ and retinoid X receptors, but not of retinoic acid receptors, and were partially blocked by an AMP-dependent protein kinase inhibitor. Circulating irisin levels were increased by 5-fold in ATRA-treated mice, linked to increased Fndc5 transcription in liver and adipose tissues, rather than skeletal muscle. Immunohistochemistry analysis of FNDC5 suggested that ATRA treatment enhances the release of FNDC5/irisin from skeletal muscle and the liver and its accumulation in interscapular brown and inguinal white adipose depots. Conclusion: These results provide new mechanistic insights on how ATRA globally stimulates FAO and enhances irisin secretion, thereby contributing to leaning effects and improved metabolic status.

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Abstract 344: FNDC5, a PGC1-a-Dependent Myokine, Increases Glucose Utilization and Fatty-Acid Oxidation by AMPK Signaling Pathway

Circulation Research ◽

10.1161/res.113.suppl_1.a344 ◽

2013 ◽

Vol 113 (suppl_1) ◽

Author(s):

Ling Tao ◽

Yi Liu ◽

Chao Xin ◽

Weidong Huang ◽

Lijian Zhang ◽

...

Keyword(s):

Fatty Acid ◽

Glucose Uptake ◽

Fatty Acid Oxidation ◽

Glucose Utilization ◽

C2c12 Cells ◽

Time Dependent ◽

Acid Oxidation ◽

Ampk Signaling

FNDC5 is a hormone secreted by myocytes that could reduce obesity and insulin resistance, However, the exact effect of FNDC5 on glucose and lipid metabolism remain poorly identified; More importantly, the signaling pathways that mediate the metabolic effects of FNDC5 is completely unknown. Here we showed that FNDC5 stimulates β-oxidation and glucose uptake in C2C12 cells in a dose- and time-dependent fashion in vitro (n=8, all P<0.01). In vivo study revealed that FNDC5 also enhanced glucose tolerance in diabetic mice and increased the glucose uptake evidenced by increased [18F] FDG accumulation in hearts by PET scan (n=6, all P<0.05). FNDC5 decreased the expression of gluconeogenesis related molecules (PEPCK and G6Pase) and increased the phosphorylation of ACC, a key modulator of fatty-acid oxidation, both in hepatocytes and C2C12 cells (n=3, all P<0.05). In parallel with its stimulation of β-oxidation and glucose uptake, FNDC5 increased the phosphorylation of AMPK both in hepatocytes and C2C12 cells in a dose- and time-dependent fashion in vitro and in vivo. More importantly, the β-oxidation and glucose uptake, the expression of PEPCK and G6Pase and the phosphorylation of ACC induced by FNDC5 were attenuated by AMPK inhibitor in hepatocytes and C2C12 cells (P<0.05). Most importantly, the FNDC5 induced glucose uptake and phosphorylation of ACC were attenuated in AMPK-DN mice (n=6, all P<0.05). The glucose-lowering effect of FNDC5 in diabetic mice was also attenuated by AMPK inhibitor. Our data presents the direct evidence that FNDC5 stimulates glucose utilization and fatty-acid oxidation by AMPK signaling pathway, suggesting that FNDC5 be a novel pharmacological approach for type 2 diabetes.

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Lipid and glycogen metabolism in the hypoxic heart: effects of epinephrine

American Journal of Physiology-Legacy Content ◽

10.1152/ajplegacy.1975.229.4.885 ◽

1975 ◽

Vol 229 (4) ◽

pp. 885-889 ◽

Cited By ~ 15

Author(s):

Crass MF ◽

GM Pieper

Keyword(s):

Fatty Acids ◽

Fatty Acid ◽

Free Fatty Acids ◽

Fatty Acid Oxidation ◽

Glycogen Metabolism ◽

Acid Oxidation ◽

Triglyceride Fatty Acid ◽

Rat Hearts ◽

Perfused Rat Hearts

The metabolism of cardiac lipids and glycogen in hypoxic and well-oxygenated perfused rat hearts was studied in the presence or absence of epinephrine. Heart lipids were pre-labeled in vivo with [1-14C]palmitate. Triglyceride disappearance (measured chemically and radiochemically) was observed in well-oxygenated hearts and was stimulated by epinephrine (4.1 X 10(-7)M). Utilization of tissue triglycerides was inhibited in hypoxic hearts in the presence or absence of added epinephrine. Hypoxia resulted in a small increase in tissue 14C-free fatty acids and inhibition of 14C-labeled triglyceride fatty acid oxidation. Epinephrine had no stimulatory effect on fatty acid oxidation in hypoxic hearts. Utilization of 14C-labeled phospholipids (and total phospholipids) was similar in well-oxygenated and hypoxic hearts with or without added epinephrine. These results suggested that the antilipolytic effects of hypoxia were predominant over the lipolytic effects of epinephrine. Glycogenolysis was stimulated threefold by epinephrine in well-oxygenated hearts. Hypoxia alone was a potent stimulus to glycogenolysis. Addition of epinephrine to perfusates of hypoxic hearts resulted in a slight enhancement of glycogenolysis.

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